The overall goal of this application is to determine the role of glutathione (GSH) adaptive responses to cigarette smoke which is a major risk factor in chronic obstructive pulmonary disease (COPD). Oxidative stress has been implicated as a pathogenic factor in the etiology of COPD. However, the role of altered GSH adaptive responses to tobacco smoke and its linkage to inflammation and oxidative stress remains unexplored. COPD is a group of lung disorders that are largely self-induced by smoking tobacco. Adaptive GSH responses are variable amongst smokers and it is hypothesized smokers who are unable to develop a robust adaptive GSH response are more vulnerable to exaggerated inflammation and injury associated with tobacco smoke. Published and preliminary data suggest that oxidative modification of histone deacetylase may also interfere with GSH adaptive pathways. Based on this, an approach to either correct the GSH imbalance or diminish oxidant burden may slow the progression of COPD. The cystic fibrosis transmembrane conductance regulator (CFTR) and breast cancer related protein (BCRP) congenic KO mouse provides a unique animal models to study defective lung GSH efflux, oxidative stress, inflammation, and injury. CFTR KO mice have a 50% decrease in their steady-state lung ELF GSH levels compared to controls and have diminished adaptive GSH efflux response to oxidative stress. The specific aims are to:1) examine mechanism(s) responsible for GSH adaptive responses stimulated by cigarette smoke;2) examine whether defective extracellular GSH adaptive responses contributes to enhanced cigarette smoke-induced lung epithelial cell oxidation and injury upon exposure to extracellular oxidants;3) Examine whether defective GSH transport sensitizes the lung to cigarette smoke-induced oxidative stress and inflammation. These studies will elucidate the role of extracellular GSH adaptive pathways as a protective mechanism in cigarette smoke-induced lung oxidation and injury and provides unique avenues for therapeutic intervention in the progression of COPD. Project Narrative: Oxidants have been implicated as a pathogenic factor in the development of emphysema. However, the role of altered antioxidant defenses to tobacco smoke and its linkage to inflammation and oxidative injury remains unexplored. These studies will elucidate the role of antioxidant adaptive pathways as a protective mechanism in cigarette smoke-induced lung oxidation and injury and provides unique avenues for therapeutic intervention in the progression of COPD.